Asymmetric Dimethylarginine, Plasma
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
The conversion of arginine to nitric oxide (NO) is catalyzed by nitric oxide synthase (NOS), and asymmetric dimethylarginine (ADMA) is an inhibitor of that enzyme. When NO synthesis is blocked, a number of regulatory processes are immediately affected, including vasodilation, platelet aggregation, monocyte adhesion, and the inflammatory pathway, amongst others.
ADMA has been of interest in cardiovascular research for several years. Increased baseline plasma ADMA levels have been reported to be a predictor of outcomes in various studies including:
-In patients with acute coronary syndrome (ACS), 2 year follow up, the hazard ratio (HR) for all-cause mortality and for myocardial infarction (MI) was 2.45 and 2.28, respectively.(1) HR is the relative risk of an adverse event.
-In diabetics referred for coronary angiography, 2 year follow up, the HR for all-cause mortality and MI was 2.63 and 2.44, respectively.(2)
-In patients with unstable angina, 1 year follow up, ADMA persistently elevated was associated with increased cardiac events.(3)
-In nonsmoking males with a previous coronary event, 5 year follow up, 4-fold increase in risk of an adverse event.(4)
However, other studies have been inconclusive or found no association with cardiac events. Furthermore, the cardiac events may be up to 13 years or more in the future.
ADMA may be particularly important in assessing cardiovascular risk in the setting of renal failure. Patients with chronic renal failure have been shown to have increased ADMA concentrations compared to healthy controls. The elevated ADMA-associated inhibition of NO has been identified as a potential causal mechanism for the high mortality rates in patients with end-stage renal disease.(5,6)
The literature data must also be assessed with a cautionary eye to the methodology used, since the inactive isomer, symmetric dimethylarginine (SDMA), can contribute to the analytical result in some procedures. Our method measures ADMA without interference from SDMA.
It is important to consider the ADMA level in the context of all other biochemical parameters, whether it is a cardiac risk marker and/or a representation of an underlying disease process itself. The NOS pathway is involved in many physiological response mechanisms, and the ADMA levels measured in plasma samples reflect an integration of the contributions from all of them. Combinations of effects can blunt or reverse the predictive value of ADMA. Other risk factors, notably smoking, alter ADMA levels in a manner that reduces its predictive value for cardiac outcomes. In one study, ADMA levels were predictive of coronary events in nonsmokers, but not in smokers, where the levels were considerably lower. The underlying reason was postulated to be the upregulation of a key ADMA metabolizing enzyme by tobacco smoke, thus driving the plasma levels down.(7)
An adjunct to other risk markers for assessing an individual’s overall probabilistic likelihood of future coronary events, especially in patients with renal failure.
This test is best used to aid in eliciting lifestyle changes that can reduce risk of coronary events; it does not predict absolute events, nor does it predict specific events.
In patients with pre-existing coronary conditions or at high risk for coronary events (diabetes, renal insufficiency), asymmetric dimethylarginine (ADMA) levels in the upper tertile, >112 ng/mL, have an increased risk for future coronary events. The arginine value is considered only in some situations, when amino acid metabolism may be altered.
Reductions in ADMA are not known to be predictive of decreased risk of future coronary effects.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
The test has no value in patients who smoke. Elevated values should not be used to diagnose the presence of disease or events.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
<18 years: not established
> or =18 years: 63-137 ng/mL
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Cavusoglu E, Ruwende C, Chopra V, et al: Relationship of baseline plasma ADMA levels to cardiovascular outcomes at 2 years in men with acute coronary syndrome referred for coronary angiography. Coron Artery Dis 2009;20:112-117
2. Cavusoglu E, Ruwende C, Chopra V, et al: Relation of baseline plasma ADMA levels to cardiovascular morbidity and mortality at two years in men with diabetes mellitus referred for coronary angiography. Atherosclerosis. 2010 May;210(1):226-231
3. Krempl TK, Maas R, Sydow K, et al: Elevation of asymmetric dimethylarginine in patients with unstable angina and recurrent cardiovascular events. Eur Heart J 2005;26:1846-1851
4. Valkonen VP, Paiva H, Salonen JT, et al: Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine. Lancet 2001;358:2127-2128
5. Ravani P, Tripepi G, Malberti F, et al: Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling approach. J Am Soc Nephrol 2005;16:2449-2455
6. Abedini S, Meinitzer A, Holme I, et al: Asymmetrical dimethylarginine is associated with renal and cardiovascular outcomes and all-cause mortality in renal transplant recipients. Kidney Int 2010 Jan;77(1):44-50
7. Maas R, Schulze F, Baumert J, et al: Asymmetric dimethylarginine, smoking, and risk of coronary heart disease in apparently healthy men: prospective analysis from the population-based Monitoring of Trends and Determinants in Cardiovascular Disease/Kooperative Gesundheitsforschung in der Region Augsburg study and experimental data. Clin Chem 2007 Apr;53(4):693-701